Chronic myeloid leukemia (CML) is a hematopoietic stem cell (HSC)-derived and progenitor-driven myeloproliferative disorder that may progress from a manageable chronic phase to an incurable blastic phase. Perrotti et al., J Clin Invest; 120: 2254-64 (2010). BCR-ABL1 is a tyrosine kinase whose constitutive activity in hematopoietic progenitors is essential for CML emergence, maintenance and progression. Most CML patients undergoing tyrosine kinase inhibitor (TKI) monotherapy achieve major or complete molecular response (CMR) with low risk of relapse or progression. However, only a few patients in CMR remain disease-free after TKI (e.g. imatinib) discontinuation. Rousselot et al., Blood 109: 58-60 (2007). Persistence of cells from the original BCR-ABL1+ clone in TKI-treated but not in allogeneic transplanted patients in CMR suggests the existence of non-proliferating (quiescent) Ph+ HSCs with innate TKI resistance, and for which BCR-ABL1 kinase activity appears dispensable. Pellicano et al., Current hematologic malignancy reports, 6: 82-7 (2011). However, how these cells persist in TKI responsive patients, and whether BCR-ABL1 expression is required for their survival/self-renewal remain unknown. Seemingly, the safety and clinical benefit of various approaches envisioning the direct killing or the induction of these Ph+ HSCs into cell-cycle as a mechanism to restore TKI sensitivity is as yet uncertain.
FTY720 (Fingolimod/Gilenya™) is an oral sphingosine analog used in multiple sclerosis (MS) patients because it acts as a reversible immunosuppressant when, upon phosphorylation, is internalized by the sphingosine-1-phosphate receptor (S1PR1). FTY720 also has a strong anticancer activity that does not require phosphorylation or S1PR1 interaction but depends on restoration of PP2A function. Neviani et al., J Clin Invest, 117: 2408-21 (2007); Roberts et al. Cancer Res; 70: 5438-47 (2010). In Ph+ leukemias, FTY720-induced PP2A activity promotes BCR-ABL1 inactivation/degradation and inhibition of survival factors (e.g. JAK2, Akt and ERK1/2). Neviani et al. Cancer Cell, 8: 355-68 (2005). This results in apoptosis of CD34+ progenitors from TKI-sensitive and -resistant Ph+ patients but not from healthy individuals, which already harbor highly active PP2A, and ultimately translates into long-term survival with normal myelopoiesis and absence of toxicity in BCR-ABL1+ leukemic mice.
The success of tyrosine kinase inhibitors depends on the addiction of Philadelphia-positive (Ph+) CML progenitors to BCR-ABL1 kinase activity. However, CML quiescent HSCs are TKI-resistant and represent an active disease reservoir. Accordingly, there is a need for compounds able to treat TKI-resistant leukemic hematopoietic stem cells.